Genetic variation in morphine analgesic tolerance: A survey of 11 inbred mouse strains

The present study assessed the analgesic potency of morphine in 11 inbred mouse strains before and after chronic morphine treatment. Using the 49°C tail-withdrawal test, significant strain differences in morphine AD₅₀ estimates derived from cumulative dose-response curves were noted prior to tolerance induction on Day 1. AD₅₀ estimates were reassessed on Day 4, after three daily systemic morphine injections for 3 days using an escalating dose schedule (10, 20, and 40 mg/kg sc). In 9 of 11 strains, morphine potency was significantly reduced from 2-fold to as much as 11-fold. Two strains (129P3 and LP) displayed no evidence whatsoever of tolerance development. Neither initial baseline withdrawal latency nor morphine analgesic sensitivity was significantly correlated with tolerance magnitude. Also observed were strain-dependent alterations (mostly hyperalgesia) in baseline tail-withdrawal latencies as a result of chronic morphine treatment. The magnitude of hyperalgesia and analgesic tolerance was significantly correlated among strains, implicating common genetic substrates and supporting their proposed association. The present work demonstrates that the presence and magnitude of morphine analgesic tolerance is genotype-dependent and identifies strains with widely divergent liabilities that should facilitate identification of trait-relevant genes.